The study of conformational equilibria and transitions in peptides and proteins is a long-standing interest of the Hermans lab, and, since several years ago, the Tropsha lab. We have developed many new approaches to doing this; the two most recently completed studies are good examples of this. In the first the new peptide growth simulation (PGS) method has been applied to describe the equilibria involved in the helix-coil transition of alanine peptides. In the second, the natural tendency of beta pleated sheet structures to assume a twisted conformation have been quantitated by a new kind of potential-of-mean-force simulation. In both cases, the ability to change the force field was exploited to gain insight into the interactions responsible for the stability of, respectively, the helix over the coil and of the twisted beta structure over the flat beta structure. A. HELIX-COIL EQUILIBRIUM (i) The helix-coil transition equilibrium of polypeptides in aqueous solution was studied by molecular dynamics simulation. The peptide growth simulation (PGS) method was introduced to generate dynamic models of polypeptide chains in a statistical (random) coil or an a-helical conformation. The key element of this method is to build up a polypeptide chain during the course of a molecular transformation simulation, successively adding whole amino acid residues to the chain in a predefined conformation state (e.g., a-helical or statistical coil). Thus, oligopeptides of the same length and composition, but having different conformations, can be incrementally grown from a common precursor, and their relative conformational free energies can be calculated as the difference between the free energies for growing the individual peptides. This affords a straightforward calculation of the Zimm-Bragg (s and s) parameters for helix initiation and helix growth. The calculated s and s parameters for the polyalanine a-helix are in good agreement with the experimental measurements. The PGS method is an effective way to study quantitatively the thermodynamics of local protein folding. (Proc. Natl. Acad. Sci. USA, 92: 10924-10928, 1995) (ii) Using molecular dynamics simulations to calculate free energies of molecular transformation, we have computed helix-coil transition free energies for alanine oligomers up to 14 residues long. The simulations have been done on the model in vacuo with dielectric constant, e = 1, 5, 25 and and on the model in solution with explicit representation of water molecules with full partial charges and with partial charges on the oligomer set to zero. In vacuo, both entropic and electrostatic contributions oppose formation of a 3-residue helical nucleus in the helix initiation step. The entropy change opposing helix growth is found to be 3 e.u., van der Waals interactions favor helix growth by 1.9 kcal/mol and electrostatic interactions favor helix growth by 3 kcal/mol (for e=1; all these values are per residue). In water, helix stability is slightly greater for the zero-charge model than for the full-charge model, i.e., the polypeptide's electrostatic interactions, which include hydrogen bonds, slightly destabilize the helix. The helix stabilizing contribution of the hydrophobic effect was found to be identical to that of the van der Waals interactions in vacuo (i.e., 1.9 kcal/mol per residue). The zero-charge model has nearly identical helix stability in vacuo and in water; the almost identical free energies of transfer of helix and coil state of the zero-charge oligomer from vacuum to water are found to be small. Thus, the results of this systematic variation of the force field afford a meaningful decomposition of the free energies for helix initiation and growth. (Biopolymers, in press.) B. BETA SHEET TWIST Twisted conformations of two- and three-stranded antiparallel b-sheet models containing alanine, glycine and valine with three or five residues per strand have been studied by molecular dynamics simulations. Free molecular dynamics and free energy simulations have been carried out to characterize the dynamics and energetics of the conformational change from a flat sheet to a twisted sheet. By altering the charges on the model in the free energy simulations, we have been able to analyze the contributions to the twist from electrostatic and van der Waals interactions. We have found that alanine and valine b-sheets prefer conformations with a right-handed twist. In contrast, model glycine sheets do not have a pronounced preference to twist. Single b-strands are found to be easily twisted, but to not have a strong preference for twisted conformations. Hence, the driving forces for the right-handed twist of b-sheets must come principaly from interactions between strands. These results disagree with several previous theoretical studies and constitute a different paradigm of the origin of b-sheet twist observed in proteins. (J. Mol. Biol., in press)